Drug delivery system

ABSTRACT

An ophthalmic drug delivery system is provided which includes at least one particle of bioerodible material, and a liquid or ointment carrier which includes ophthalmic drug to be delivered to the ocular area. A process of making the system and a method of treatment are also provided.

BACKGROUND AND SUMMARY OF THE INVENTION

The invention relates to a drug delivery treatment system and method ofmaking the system and method of treating the eye.

Most ocular treatments require frequent topical administration of drugsto the tissues of the ocular cavity.

When medication must be applied topically to the eye, one common form oftreatment is the use of liquid drops. The liquid drop form is extremelyeasy to use as the patient merely self-administers the liquid through aneye dropper or dispenser which includes an eye drop extension end.However, a substantial disadvantage of the liquid form is that themedication or lubricating solution rapidly drains from the ocular cavityinto the nasal cavity through an opening called the punctum. Further,the liquid may simply evaporate from the eye.

Thus, with the use of liquid treatments, a continuous prolonged deliveryof medication is not achieved, and the exact dosage is unpredictable asliquid drains out of the eye. Even with intermittent administration, theliquid treatment will continue to rapidly wash out of the eye, and thecontinued problem of unpredictability of dosage remains. Further,continuous administration of liquid is not only inconvenient, but may bedangerous.

Several systems shown in U.S. patents provide large ocular inserts todeliver drug to an eye continuously. Certain inserts disperse the drugand require removal of the carrier of the drug once the drug has beendelivered. However, U.S. Pat. Nos. 3,845,201; 4,164,559 and 4,179,497show various inserts in the form of large pellets which dispense drugover a period of time and eventually are completely eroded, and thus donot require removal after drug delivery.

These inserts have certain advantages over the liquid treatments as morepredictable dosage is obtained as there is a continuous dispensing ofthe drug over a period of time without rapid washout. Thus, the unitaryocular inserts provide predictable dosage over a period of time withoutthe requirement of repeated applications as required with liquidtreatments.

However, there are certain disadvantages which accompany the use oflarge unitary ocular inserts. These unitary inserts must be carefullyplaced under the eyelid, and require special care and special insertdevices for insertion. Difficulties in patient education for insertingthese in compliance with proper technique have prevented theirwidespread use.

In an attempt to address the problems of liquid treatments and ocularinserts, U.S. Pat. Nos. 3,914,402; 4,001,388 and 4,115,554 all to Shell,show ophthalmic forms which include a suspension of solid particles from10 to 300 microns in largest dimension in a liquid medium. The liquidmedium in the Shell patents is used exclusively as a carrier forsuspending the particles and delivering the particles to the eye. TheShell dosage form alleviates certain problems associated with ocularinserts, including the complication of insertion and requirement forspecial insertion devices. However, the liquid carrier in Shell does notinclude drug therein, and therefore, the liquid does not deliver drug tothe ocular environment. Only the minute particles can be relied on fordrug delivery. Treatment with the Shell patent system depends on thechance of the particles becoming lodged in the eye tissue, as the liquiddelivers no drug. Further, as no drug is included in the liquid, all themedication which is limited to inclusion in the particles, couldfeasibly wash out of the eye with the particles through the punctumwhich is about 0.5 mm in diameter. Thus, Shell may effectively deliverno drug at all to the ocular environment, as the particles may drain outof the eye prior to release of the medication from the particles.

Although Shell asserts that the particles do not drain from the ocularcavity through the punctum, in practice if the particles aresubstantially smaller in diameter than the punctum, these particles willwash and drain out of the eye in the normal course of drainage of thesuspension liquid through the natural duct system of the ocular cavity.As the particles in Shell are delivered in a liquid suspension, theexcess liquid delivered to the eye would naturally drain through thepunctum. Further, liquid Contact alone with the eye would provide nomedication to the ocular environment as the liquid is free ofmedication.

U.S. Pat. No. 3,826,258 to Abraham shows a gradual release medicinecarrier. Abraham addresses topical treatment of the eye using capsuleswhich are dropped into the eye. Similar to the Shell system, the liquidcarrier in the Abraham patent is used merely to suspend the capsules anddeliver the capsules to the eye. Abraham neither shows nor suggestsincluding drug in the liquid carrier solution.

Thus, an object of the present invention is to provide a drug deliverysystem, a method of making the drug delivery system and a method oftreatment which includes the advantages of drug solution treatments,insert treatments and suspension treatments.

It is a further object to provide a treatment system method whichdelivers a dependable dosage or amount of treatment media to the eye. Itis a further object to provide an ophthalmic treatment system easilyadministered to the eye which will remain in the ocular cavity over aperiod of time.

It is yet another object to provide a system which provides prolongeddrug delivery as well as instant delivery of drug to the eye.

These and other objects are achieved by providing an ophthalmic drugdelivery system which includes at least one particle of bioerodiblematerial. The particle or particles are suspended in one of a liquidcarrier and an ointment carrier containing ophthalmic drug and having apH acceptable to the eye.

The drug delivery system provides prolonged delivery of drug to the eyeas drug in the solution is absorbed into the particles of bioerodiblematerial prior to administration and/or after administration to the eye.The drug absorbed in the bioerodible material will be released over aperiod of time as the particles erode in the ocular environment.Further, an instant delivery of drug to the eye is provided by the drugin the liquid or ointment carrier. Thus, where instant delivery isneeded, the liquid carrier provides instant release of drug and theparticles provide prolonged release of drug.

According to other advantages of certain preferred embodiments of theinvention, the particles can include drug dispersed therein prior tosuspension into the carrier solution. Thus, in certain preferredembodiments a different drug can be provided in the particles forprolonged administration than the drug contained in the liquid medium.Further, according to certain preferred embodiments, the concentrationof drug in the particles is such that when placed in a carrier solutionhaving a different drug, the equilibrium between the two will be suchthat drug in the carrier solution will absorb into the particles. Thus,the particles will include different types of drug disposed therein forprolonged delivery.

According to other advantageous features of certain preferredembodiments of the invention, the specific equilibrium between drug inthe particle and drug in the carrier liquid provides a specific amountof drug in the particle to be delivered over a specific duration whenadministered to the ocular area.

Methods for making the drug delivery system and methods of treating theeye using the drug delivery system are also provided.

Other objects, advantages and novel features of the present inventionwill become apparent from the following detailed description of theinvention when considered in conjunction with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a magnified view of the particles of bioerodible materialaccording to certain embodiments of the present invention;

FIG. 2 is a magnified view of particles of the bioerodible materialaccording to other advantageous embodiments of the present invention;and

FIG. 3 is a pictorial view showing administration of the ophthalmictreatment system into the conjunctival sac of the eye.

DETAILED DESCRIPTION OF THE DRAWINGS

In its simplest form, the present eye treatment system includesparticles of bioerodible material, which are suspended in a liquidcarrier or ointment carrier having at least one drug therein and havinga pH acceptable to the eye. The liquid medium employed in the presentsuspension system may be an aqueous or non-aqueous ophthalmicallyacceptable sterile liquid. Suitable non-aqueous liquid media include thephysiologically acceptable oils such as silicon oil, USP mineral oil,white oil, and vegetable oils, for example, corn oil, peanut oil or thelike.

To achieve a uniform dispersion of the particles in the liquid, thedensity of the liquid medium can be chosen such that it is equal to thedensity of the particles. Therefore, the particles will not float to thetop of the liquid or sink to the bottom. If the liquid medium does nothave the same density of the particles, the viscosity of the liquidmedium can be adjusted in order to provide a uniform dispersion, or thedispensing system can achieve a dispension by shaking or proper mixingimmediately before administration.

In certain embodiments, the eye treatment liquid medium contains avariety of other materials to adjust pH, render the medium isotonic,preserve the treatment system and the like. Preservative agents whichcan be used include benzalkonium chloride in a concentration range offrom 1:15,000 to 1:30,000; chlorobutanol in a concentration range offrom 0.3% to 0.8%; thimerosol in a concentration range of from 0.001% to0.003%; and phenyl mercuric nitrate in a concentration range of from1:60,000 to 1:80,000. Also, in certain preferred embodiments,unpreserved unit or daily dose systems can be used. Other agents may beadded to increase viscosity, promote suspension and/or improve ocularcompatibility, such as methyl cellulose in an amount of from 0.1% to0.7% or poly (vinyl alcohol) in an amount of from 0.4% to 2.0%. Theseand other additive materials are known in the art. A variety of thesematerials is generally described in the book Contact Lens Practice,Robert B. Mandell (Charles C. Thomas, 1965) at pp. 159-165, whichdescription is herein incorporated by reference.

In certain preferred embodiments, instead of using a liquid medium forthe suspension, the particles can be suspended in an ointment such aslanolin, petrolatum and other known ointments.

Medication or drugs are included directly in the liquid or ointmentcarrier. The term "drug" is used in this description in its broadestsense, and covers all drugs used in any mammal. Drugs which are usefulin the ocular area are specifically desired, although the presentinvention is not limited to only ocular drugs. The term "drug" isdefined in the present invention as including, but not limited to thefollowing classes of drugs: therapeutic drugs, preventative drugs,diagnostic drugs and any other drugs. It is to be understood that avariety of classes, subclasses and specific examples of drugs notexpressly mentioned herein are within the scope of this invention andother examples of drugs are well known and are easily ascertainable tothose skilled in the art.

Drugs suitable for incorporation in the particles of the suspension,consistent with their known dosages and uses, are without limitationophthalmic drugs including: antibiotics such as tetracycline,chlortetracyline, bacitracin, neomycin, polymyxin, gramicidin,oxytetracycline, chloramphenicol, gentamycin, penicillin, kanamycin,amikacin, sisomicin, tobramycin, garamycin, ciprofloxacin, norfloxacinand erythromycin; antibacterials such as sulfonamides, sulfacetamide,sulfamethizole and sulfisoxazole; antivirals, including idoxuridine; andother antibacterial agents such as nitrofurazone and sodium propionate;anti-allergenics such as antazoline, methapyriline, chlorpheniramine,pyrilamine and prophenpyridamine; anti-inflammatories such as cortisone,hydrocortisone, hydrocortisone acetate, dexamethasone, dexamethasone21-phosphate, fluocinolone, medrysone, prednisolone, methylprednisolone,prednisolone 21-phosphate, prednisolone acetate, fluorometholone,betamethasone, fluocortolone, indomethacin and triamcinolone;decongestants such as phenylephrine, naphazoline and tetrahydrazoline;miotics and anti-cholinesterases such as pilocarpine, eserinesalicylate, carbachol, di-isopropyl fluorophosphate, phospholine iodide,echothiophate, physostigmine and demecarium bromide; mydriatics such asatropine sulfate, cyclopentolate, homotropine, scopolamine, tropicamide,eucatropine, and hydroxyamphetamine; sympathomimetics such asepinephrine and immunosuppressants such as cyclosporin and azathioprine.

According to certain preferred embodiments, drug is included in theparticles prior to suspension in the carrier. The drug in the particlescan include the same drug as the drug in the carrier and/or differentdrugs. As will be discussed below, the drug can be dispersed throughoutthe particles or encapsulated within the particles.

The particles suspended in the liquid or ointment medium should be madeof material which is bioerodible such that removal of the particles fromthe eye is not required as they are broken down and absorbed in theocular environment (or resorbed). The term "bioerodible" is defined as amaterial which innocuously disintegrates or breaks down from a unitstructure or enclosure over a prolonged period of time in response tothe environment of the eye by one or more physical or chemicaldegradative processes, for example, enzymatic action, hydrolysis, ionexchange, dissolution by solubilization, emulsion formation or micelleformation. The bioerosion of the particles not only prevents a build-upof particles in the tissues of the ocular cavity, but also providesprolonged release of the treatment in the eye which can be controlledsuch that the treatment is predictable.

Bioerodible materials used in the particles of the present suspension ofthis invention should be non-toxic and compatible with any drug whichmay be delivered therewith. In certain preferred embodiments, thebioerodible materials should be capable of absorbing drugs in which theyare soaked, and in certain other preferred embodiments, the bioerodiblematerials should be capable of forming films which wholly surround andenclose a drug or other active agent to be delivered to the eye.

The particles should be comfortable when they are under the eyelids, aswell as when they are on the surface of the eye in between the eyelidsin the interpalpebral area, for example. In certain preferredembodiments, the particles are soft to help assure this comfort.

There are several naturally occurring materials, as well as syntheticmaterials, which are biodegradable and suitable for the presentinvention.

Examples of synthetic polymers that can be prepared which arebiodegradable include polylactides and polyglycolic acid. Thesebiodegradable polymers are broken down into innocuous products such atcarbon dioxide and water and they are also commercially available.

Useful polylactides includes both homopolymers and copolymers. Usually,these polylactides are prepared from the cyclic esters of lactic acids.Both L(+) and D(-) forms of lactic acid may be used to prepare thepolylactides as well as the optically inactive DL-lactic acid mixture orany desired mixtures of D(-) and L(+) lactic acids.

Lactide copolymers offer an mmportant degree of flexibility in choosingthe life of a polymer matrix since this can be controlled through theamount and type of comonomer used. Some illustrative examples ofsuitable comonomers include: glycolinde, β-propiolactone,tetramethylglycolide, β-butyrolactone, gamma-butyrolactone,pivalolactone, and intermolecular cyclic esters of α-hydroxybutyricacid, α-hydroxyisobutyic acid, α-hydroxyvaleric acid,α-hydroxyisovaleric acid, α-hydroxycaproic acid, α-hydroxy--ethylbutyric acid, α-hydroxyisocaproic acid, α-hydroxy1β-methylvalericacid, α-hydroxyheptanoic acid, α-hydroxyoctanoic acid, α-hydroxydecanoicacid, α-hydroxymyristic acid, α-hydroxystearic acid, α-hydroxylignocenicacid, and β-phenyllactic acid.

Methods of preparing polylactides are well documented in the patentliterature. The following U.S. Patents, the teachings of which arehereby incorporated by reference, describe in detail suitablepolylactides, their properties and their preparation: Dorough, No.1,995,970; Schneider, No. 2,703,316; Salzberg, No. 2,758,987; Zeile, No.2,951,828; Higgins, No. 2,676,945 and No. 2,683,136; Trehu, No.3,531,561; British Patent Specifications Nos. 755,447; 799,291; 825,335;901,037; 932,382; 1,048,088; 1,123,445; West German Patents Nos.946,664; 975,191; 1,112,293; 1,152,258; 1,153,902; East German PatentNo. 14,548; French Patent Nos. 1,425,333; 1,478,694; 1,512,182;Netherlands Patent No. 99,836; Netherlands Patent Application Nos.6,605,197; 6,605,292; Japanese Numbers 17,675 (1966); 7,796 (1967);2,948 (1968); 15,789 (1969).

Polyglycolic acids have recently been found to possess excellentbiodegradable properties. Polyglycolic acid is the homopolymer ofglycolic acid (hydroxyacetic acid). In the conversion of glycolic acidto polyglycolic acid, glycolic acid is initially reacted with itself toform the cyclic ester glycolide, which in the presence of heat and acatalyst is converted to a high molecular weight linear-chain polymer.Polyglycolic acids and their properties are described in more detail inthe following article, the teachings of which are hereby incorporated byreference: "Cyanamid Research Develops World's First SyntheticAbsorbable Suture", Chemistry and Industry, July 11, 1970, page 905.

The molecular weights of polypeptides and polyglycolic acid are closelyrelated to both the exudation of the drug and the biodegradation of thematrix. It has been found that high molecular weights, i.e., Mw=90,000or higher result in polymer matrices which retain their structuralintegrity for longer periods of time, while lower molecular weights,i.e., Mw=30,000 or below, result in both slower exudation and shortermatrix lives.

A preferred particle material is collagen such as that obtained from pigsclera or cow skin and cross-linked with ultraviolet, or other forms ofcollagen cross-linked either by ultraviolet or X-ray.

The chemistry of a molecular structure and biochemical properties ofcollagen have been well established. The use of collagen as a vehiclefor drug delivery as a bio-material is well known. U.S. Pat. No.1,464,559 to Miyata et al. lists several publications discussing the useof collagen in drug delivery. An example is "Annual Review of Biophysicsand Bioengineering", Vol. 3, pp. 231-253, 1974, by Miyata et al. Anotherexample is Rubin et al., J. Clin. Pharmacol., Vol. 13 (8/9):309-312(1973), "Collagen as a Vehicle for Drug Delivery".

Collagen is a major protein of connective tissue such as cornea, skin,etc., and can be solubilized and purified by the treatment withproteolytic enzymes (other than collagenase) such as pepsin. Solubilizedollagen is telopeptides-poor, relatively inexpensive, not antigenic anduseful as a biomedical material. Enzyme solubilized native collagen issoluble in acidic pH, and soluble at physiological pH and at bodytemperature.

Native collagen is insoluble at physiological pH and at bodytemperature. Thus, native collagen must be changed such that thecollagen erodes in the ocular environment so that physical removalthereof is not required.

The U.S. Patent to Miyata et al. shows various forms of chemicallymodified collagen which is erodible in the eye under physiological pHand under normal body temperatures.

Another material which can be used for the particles of the presentinvention is gelatin which is obtained by the selective hydrolysis ofcollagen and includes a complex mixture of high molecular weight watersoluble proteins.

As used herein, the term cross-linked gelatin means the reaction productof gelatin or a gelatin derivative with a cross-linking agent which isreactive with either the hydroxyl, carboxyl or amino functional groupsof the gelatin molecule but is substantially unreactive with the peptidelinkages of the gelatin molecule. The product of cross-linking reactionpreferably has an average molecular weight of from 20 to 50,000 betweencross-links, while higher values can also be employed. These reactionproducts bioerode in the environment of the eye over a prolonged periodof time.

Cross-linked gelatin materials and their preparations are well known.The degree of gelatin cross-linking is dependent upon the processingconditions employed and markedly affects the gelatin's bioerodability.Exemplary cross-linking agents are: aldehydes, such as monoaldehydes,e.g., C₁ -C₄ aldehydes, dialdehydes, epoxides, para-benzene quinone, andaqueous peroxydisulfate.

Aldehydes and ketones, especially the 1 to 4 carbon aldehydes andketones are preferred, with formaldehyde being a most preferredcross-linking agent.

Irradiation is another suitable method for cross-linking gelatin; seefor example Y. Tomoda and M. Tsuda, J. Poly Sci., 54,321 (1961).

The reactive hydroxyl, carboxyl and amino groups are respectivelypresent in gelatin in the appropriate amounts of 100, 75 and 50 meq per100 grams. These quantities may serve as a general guide in determiningthe amount of cross-linking agent to be used.

Cross-linked gelatin is relatively permeable to ocular fluid so thatdiffusion of drug through gelatin may take place to some extent. Thus,cross-linked gelatin is a good example of a release rate-controllingmaterial which releases drug by adiffusion mechanism.

Other materials which can be used for the particles include polymers ofpolyvinyl alcohol, methyl cellulose, carboxy methyl cellulose,hydroxypropy methylcellulose and lipids, which may include licithin,cholesterol, fatty alcohols and other related materials. Particles canalso include methyl cellulose derivatives and can include a combinationof the bioerodible materials discussed above. Further, treatment systemcan include a variety of different types of particles having differentcomponents to thereby vary the rate of erosion. Further, certainbioerodible materials may be more advantageous for absorbing andreleasing certain active agents to be delivered to the eye.

Crystallinity also affects the exudation and biodegradability rates. Thepolymer matrices having higher degrees of crystallinity have slowerexudation rates and slower biodegradability. It is known that thecrystallinity has a marked effect on physical properties. See Flory,Paul J., Principles of Polymer Chemistry, 5the printing, 1966 at pp. 49et seq. It has also been reported in the literature that gaseousdiffusion through polymeric membranes is slower, in general, for thosepolymers having higher degrees of crystallinity. See Michaels, A. S. andBixler, H. J., "Flow of Gases through Polyethylene and RubberyPolymers," J. Poly. Sci., vol. 50, pp. 413-439 (1961).

A good amount of control over the release of drug can be obtained bychoosing appropriate molecular weights and degrees of crystallinity inthe polymer matrix. For example, if a relatively long release durationis desired, a high molecular weight polymer formed from a pure opticalisomer of lactic acid can be used for the matrix; on the other hand, ifa rapid release rate is desirable over a short duration, a low molecularweight lactide copolymer having a lower degree of crystallinity can besynthesized for use as the polymer matrix. Those skilled in the art willknow or be able to determine by routine experimentation many suitablecombinations of molecular weights and degrees of crystallinities ofpolylactides or polyglycolic acid to accomplish a desired release rateand duration.

Using one or more of the above parameters, polymeric matrices can bedesigned which have a great variety of exudation rates andbiodegradability. Matrices can be synthesized to have lives shorterthan, equal to or longer than the period of effective drug delivery. Forthe shorter matrix lives, drug delivery will be accomplished by acombination of drug exudation and matrix biodegradation; for the longermatrix lives, drug delivery will be substantially dependent on only drugexudation. The degree of flexibility thus offered in designing drugdispensing system of this invention is of great significance.

Further, the particles of the present invention, according to certainpreferred embodiments, should be soft and malleable such that pressurecreated by the eyelid and the eye will deform the particles. In certainpreferred embodiments, the particles can actually be in a semi-solidform as long as the particles do not dissolve in the liquid or oilmedium in which they are suspended before administration to the eye.

Preferred methods for forming semi-solid particles include hydratingsubstances such as gelatin, collagen or polymers immediately beforeinsertion or placing soft hydrated solids in a mixture or ointment basethat will not permit them to dehydrate.

Hydration is generally performed by exposure of the particles to anaqueous solution such that water is incorporated into the particles. Theparticles should remain hydrated when administered to the patient.

The bioerodible material particles can be hydrated by placing thematerial in the aqueous solution carrier discussed above. The aqueouscarriers will hydrate the particles, and if the particles are left inthe carrier, dehydration will be prevented.

Also, the bioerodible material can be hydrated by placing it in a drugsoaking solution. Dehydration is prevented by placing the drug soakedparticles in the aqueous carrier or in an ointment carrier. Whendispersed in the ointment, the water will be retained in the particlesand dehydration will thus be prevented by the ointment carrier.

When lipid is used a the bioerodible particle material, hydration is notnecessary as lipid is already in a soft, malleable form.

Other methods for making materials which can be used for the particlesof the invention malleable in form are known.

Although plasticizers are not the most preferred means to provide soft,malleable particles, examples of plasticizers which can be used in thepresent invention are shown in U.S. Pat. No. 4,179,497 to Cohen et alwhich shows large bioerodible inserts. A requirement of any plasticizersused is that the material be completely soluable in the ocularenvironment. Examples of suitable plasticizers include water,polyethylene glycol, propylene glycol, glycerine, trimethylol, propane,di and tripropylene glycol, hydroxypropyl sucrose and the like.Plasticizers can be present in the particles in various ranges. Althoughnot the most preferred method of providing softness and malleabilitywhen plasticizers are used, they should be used in the lowestconcentration possible and not greater than 20%.

Cohen et al recites a method of plasticizing a solid insert product withwater. As applied to the present invention, the particles are contactedwith air, having a relative humidity of at least about 40% until theparticles pick up at least about 5% water, thereby becoming softer andmore pliable. In certain preferred embodiments, the relevant humidity ofthe air is from about 60% to about 99% and the contact is continueduntil the water is present in the particles in amounts of from about 10%to about 20%.

Any bioerodible material which is compatible with any drug dispersedtherein, is non-toxic, has the desired encapsulation properties orproperties for dispersion of drug throughout, and has appropriatediffusion and erosion properties might also be used. The materialsdiscussed above are examples of preferred embodiments, but should in noway limit the materials used for the particles of the presentsuspension.

There are several processes which can be used to form the bioerodibleparticles of the present invention.

One method includes using a liquid or a mixture of the bioerodiblematerial which is poured onto a flat surface. The film created is thenallowed to dry as the solvent evaporates. Once the film has dried, theindividual particles can be cut using known methods. A variety ofmethods can be used to cut the film into individual particles. Accordingto most embodiments, this cutting can be done by a preformed mold cutterhaving the proper dimensions.

These dimensions of the particles can be controlled during the particleforming process. For example, the thickness can be controlled bypreparing the proper fluid phase of the bioerodible material. As anexample, a solution of gelatin, collagen or carboxy methyl cellulose,for example, can be dried and then cut to the specific shape anddimensions or allowed to dry in appropriate molds.

According to certain preferred embodiments, the liquid mixture ofbioerodible material is poured into a shallow pan or half-mold to thedesired thickness. In certain embodiments, the pan or mold can includemarkings around the sides to indicate the thickness poured. In this way,the proper thickness can be assured. Subsequent to drying the particlesare then cut in the remaining two dimensions.

In certain embodiments the liquid phase of the bioerodible material isnot hydrated (the solvent is not aqueous). Further, even if the liquidphase is hydrated during pouring, the film or mold-forms aresubsequently dehydrated when dried. In certain embodiments, the film orcut particles should be subsequently hydrated by soaking in an aqueoussolution. The hydrated film or particles will expand to a certain degreedepending on the amount of water incorporated therein. Thus, whendetermining the thickness of the film of bioerodible material which isnot hydrated, the expected increase of thickness due to hydration shouldbe compensated for by pouring a thinner film.

According to a separate application of the present invention, thespecific dimensions of the bioerodible particles are chosen such thatcertain optimum treatment conditions are met. A system which providesthese specific dimensions is the subject matter of a patent applicationfiled on same date. In this unique system, the particles are formed witha greatest dimension of at least 0.5 mm, and a smallest dimension of nomore than about 0.4 mm to 0.7 mm when disposed in the ocularenvironment.

Due to the specific minimum size of the largest particle dimension, thepresent invention provides optimum prevention of drainage through thepunctum, and thus provides optimum prolonged delivery, as well as apredictable dosage that will remain in the eye. It should be noted thatthis specification is merely a minimum, and it is contemplated that thelargest dimension be 4 mm or even greater to maximize the amount ofmaterial delivered. At the same time, due to the specific size of thesmallest particle dimension in the ocular environment, the treatmentsystem will not be uncomfortable or irritate the eye.

Further, if the particles are soft and malleable, such as when they arehydrated, the smallest dimension prior to administration to the eye canbe increased above the preferred range. The soft material will be lessirritating to the eye. Further, if placed between the eyelid and theeye, the particles will be compressed to the proper non-irritable rangeby the pressure between the eyelid and the eye. Also, as the particlesare soft, they should conform to the eye and be comfortable even whendisposed between the upper and lower eyelids. Thus, the thickness of thepoured film can be increased when the particles are to be softened andthus malleable.

In certain preferred embodiments, the preferred hydrated thickness(smallest dimension) is in the range of about 0.5-0.75 mm. However, ifmalleable, especially if semi-solid in form, the smallest dimension canbe up to 1 mm if administered to the eye between the eyelid and the eyewhere pressure will compress the particles to the proper thickness.

Pouring of the film is but one method of controlling the thickness.Other methods include pouring into molds of the proper dimension, andcutting dried masses of the material to the proper thickness. The methodof forming the particular thickness should not be limited to theexamples given above. Regardless of the method for forming the properdimensions, the preferred ranges for this unique application of thepresent invention's unique dimensions are discussed below. Further,although these dimensions are preferred for certain applications, thepresent invention should in no way be limited to these dimensions.

In these embodiments, the smallest dimension of the three-dimensionalparticles should have a thickness of no greater than about 0.4 mm to 0.7mm when placed in the ocular environment. Depending upon the compositionof the particles, if compression of the particles is not expected in theocular environment, the particles should be either cut to this specificsmallest dimension, or have a film thickness of this dimension. However,in preferred embodiments, the bioerodible particles are made such thatthey are malleable, and thus can be cut to a size larger than the givenrange of the smallest dimension, as long as the particles will bedeformed and compressed to the proper size range by the pressure betweenthe eyelid and, the eye. These methods of making the particles malleableare discussed above. Although the exact dimensions vary according to thespecific materials and degree of deformation associated therewith,according to certain preferred embodiments, the particles that will becompressed should be cut such that the smallest dimension is no greaterthan 0.4 to 1.0 mm prior to administration to the eye, and should becompressed to the range of no more than 0.4 to 0.7 mm in the ocularenvironment.

The largest dimension of the particles should be at least 0.5 mm. Thedrainage system of the eye includes the punctum which is an opening oraperture on the radial aspect of both upper and lower eye lid margins(in the medial corner of the upper and lower eyelids). The punctum hasan average diameter of 0.5 mm. The punctum provides an opening into thedrainage ducts or the lacrimal canaliculi of the drainage system whichprovides drainage of material out of the eye area. Material leaves thecanaliculi, and passes through the lacrimal sac and nasolacrimal duct.Thus, the largest dimension of the particles should be greater than thesize of the punctum to hinder drainage of the particles out of the eyethrough the punctum. It should be noted that 0.5 mm is merely a minimumvalue of the greatest dimension, and according to certain preferredembodiments, the largest dimension is generally 1 to 2 mm, but can be 4mm or even greater to maximize the amount of material delivered. Incertain preferred embodiments the third dimension or width should beabout 0.5 mm or greater which further prevents drainage of the particlesthrough the punctum.

The balance of the two dimensions as discussed above provides a systemwhich will not drain from the eye area, and which will at the same timereduce the chance of injury or irritation to the eye even though thesystem includes particles large enough such that drainage through thepunctum is prevented. Thus, prolonged, continuous treatment is providedwithout irritation of the eye and without need for meticulousapplication requiring special insertion devices.

However, as discussed above, the present invention should in no way belimited to these specific dimensional confines. It is contemplated thatsmaller particles be included in the present drug suspension, and it isalso contemplated that larger particles be included in the presentsuspension. The only size requirement is that the particles can besuspended in a liquid or ointment carrier and subsequently administeredto the eye in the suspension.

The particles can have any shape, including but not limited to: spheres,hemispheres, flat discs of any polygonal configuration, rounded discs,egg-shaped particles, cylinders, rods, elongated spaghetti-like forms,elongated box-forms, elongated ribbon forms and others.

As discussed above, in certain preferred embodiments, drug is dispersedthroughout the particles prior to suspension in the carrier. Thisdispersion of the drug can include placing the drug component in thefluid form of the bioerodible material prior to forming the film, mixingthe drug throughout and then pouring the film which is eventually cutinto particles. According to other advantageous embodiments, the drug isadded to the particles after cutting from the film. In theseembodiments, the cut bioerodible particles are soaked in drug solution,and thereby absorb the drug. After the drug has been included in thebioerodible particles, the particles can then be suspended in the liquidmedium.

It is contemplated that the amount of drug in the particles can bevaried by soaking the particles in different concentrations of the drug.Further, different types of bioerodible material will absorb drug tovarying extents. Thus, the amount of drug can be varied by usingdifferent types of bioerodible materials. Further, by varying thedensity of the particles, drug will be absorbed to different extents.For example, by increasing the particle material density, drug will beabsorbed to a lesser degree than with a material less dense.

FIG. 1, shows a form of the particles 10 having bioerodible material 12and drug 14 dispersed throughout according to certain preferredembodiments of the invention.

The drug can also be encapsulated inside an outer coating of thebioerodible material. Encapsulation can be achieved by casting. The drugcan be added to the bioerodible material while it is in liquid orparticle form and the mixture can be reduced to fine microcapsules bygrinding or other methods. Alternatively, fine particles of the drug canbe coated such as by suspending dry particles of the drug in an airstream and contacting that stream with a stream of bioerodible materialthat coats the material with a wall of bioerodible material.

Another suitable microencapsulation method is the co-ascervationtechnique. The co-ascervation technique includes formation of threeimmiscible phases, a liquid manufacturing phase, a core material phaseand a liquid coating phase. Liquid coating is deposited on the corematerial and rigidized usually by thermal, cross-linking or desolvation.

Encapsulated particles 20 are shown in FIG. 2, with a coating 12 ofbioerodible material surrounding drug 14 according to certain preferredembodiments.

Once the particles are formed, they are then suspended in the liquid orointment medium 16 (shown in FIGS. 1 and 2). The treatment system caninclude different types of particles having different drugs dispersedthroughout. Further, the treatment system can include different types ofbioerodible material in the particles such that a differentiated rate oferosion can be achieved, thus providing a time release system forcontinuous long-term release of material to the eye.

Although clearly not limited to the following range, approximately 5 to10 particles should be included in each dose. However, this dose canchange depending upon the size of the particles, the concentration ofthe drug, the type of drug, the treatment required for the specificpatient, or for the specific condition. The particles in suspension canbe included in a conventional eye dropper bottle which provides forsimple self-administration. According to certain preferred embodiments,the particles are included in a single dose container. Thus, the entiredosage is included in a single container with a dispensing end which thepatient opens and then drops the suspension into the eye. Thus, properdosage is assured. As discussed above, the density of the liquid mediumor the viscosity of the liquid medium can be used to assure uniformdispersion of the particles in the liquid medium or uniform dispersioncan be provided by shaking immediately preceding administration.

According to the present invention, the liquid or ointment mediumincludes drug therein. Thus, the particles can include drug dispersedtherein, as well as drug dispersed throughout the solution. Medicationis immediately delivered to the eye in the solution and a prolongeddosage is provided by the bioerodible particles. If an immediate highconcentration of drug is needed, a high concentration of drug in thesolution can be provided. Further, it is contemplated to use particleshaving a drug dispersed therein different than the drug included in thesolution. Thus, for different situations, drugs which are advantageouslyprovided in a solution in a high dosage and which are not necessarilyrequired over a period of time can be included in the solution andprolonged dosage of another drug can be provided in the particles.

In certain preferred embodiments, particles are dispersed in a standardeye ointment vehicle. The ointment can then be administered to the eyeusing standard procedures, For example, the lower eyelid is lifted outwhile the patient is looking up, and the ointment is then applied in theconjunctival sac. The lids should be closed for about one minute toallow the ointment to melt.

According to other advantageous features, a specific bioerodiblematerial could be used which absorbs drug in relation to theconcentration of the drug in which it is suspended. Thus, a single typeof bioerodible material particle could be put into differentconcentrations of drug and thus provide different dosages of drugdepending on the concentration in which it was suspended. Such abioerodible material is placed in a solution including drug, andequalibrium between the particles and the solution would determine theexact concentration and duration of action.

The following examples are offered by way of illustration only andshould not be construed as limiting the scope of the present inventionin any way.

EXAMPLE I

A. A suspension of cross-linked collagen particles is prepared asfollows:

Nine grams of collagen are added slowly with stirring to 40 grams ofbuffer solution at 90° C. The buffer solution includes one liter ofdistilled water, 7.1 grams of disodium hydrogen phosphate and 6.9 gramsof sodium dihydrogen phosphate monohydrate. The pH should be 6.8. FortyMl of the phosphate buffer and 0.15 grams chlorobutanol are combinedwith the heating and stirring. Alternatively, the collagen can be addedto the buffer solution after it is cooled to room temperature and themixture is then heated to 90° C. until the solution is complete.

The mixture is stirred thoroughly for four minutes until the temperaturefalls to 40° C. and is then poured onto a sheet of polyvinylchloride toa thickness which will give a dry thickness in the range generally ofabout 0.4 mm to 0.7 mm. The resulting film is dried at room temperaturefor one day.

A solution of formaldehyde (1% by weight) is prepared by addition of13.1 grams of 38 percent formaldehyde reagent to 487 grams phosphatebuffer (pH 6.8). The collagen films are submerged in this bufferedformaldehyde solution for 20 minutes at room temperature, quickly rinsedwith water and soaked in ice water for 2 hours. The films are removedfrom the ice water and dried overnight.

The dried film is then cut into individual particles using a moldcutter. The mold cutter forms disc-shaped particles having a diameter of1.0 mm, and a thickness of 0.4 mm which was the thickness of the driedfilm.

B. The particles are then placed in a solution of tobramycin at 25° C.for 15 minutes. Concentration of drug in the solution is 40 mg per ml.The particles will absorb the drug solution.

The particles are then removed from the solution and allowed to dry for2 hours.

A liquid medium made of sterile distilled water, 1% w. poly (vinylalcohol), 0.004% benzalkonium chloride and 0.1% tobramycin is prepared.

A suspension of about 5 particles per 0.25 cc carrier medium isprepared. The drops of the suspension can be administered from adispenser 30 by dropping the suspension into the eye. Specifically, incertain embodiments, the lower eyelid 32 is pulled down and thesuspension 34 is dropped into the area 36 between the eyelid 32 and theeye 38 as shown in FIG. 3. One administration containing from about 3 to6 particles will provide continuous delivery of tobramycin for about 6hours.

EXAMPLE II

The particles for the suspension are prepared as described in ExampleIA. The particles are then suspended in a liquid medium made of steriledistilled water, 1% w poly (vinyl alcohol), 0.004% benzalkonium chlorideand 0.1% dexamethasone. The suspension should be about 5 particles per0.25 cc. The particles should be suspended for at least 20 minutes priorto administration.

The suspension described above is administered to the patient asdescribed in Example IB.

EXAMPLE III

The particles for an ointment suspension are prepared as described inExample IA. The particles are then placed in a solution of garamycin at25° C. for 20 minutes. Concentration of drug in the solution is 40 mgper milliliter. The particles will absorb the drug solution.

The particles including garamycin are then suspended in an ointment ofpetrolatum including 0.1% garamycin (40% solid petrolatum, 60% liquidpetrolatum).

The ointment described above is administered to the patient using a tubewith a wide dispenser opening.

EXAMPLE IV

The treatment suspension is prepared as described in Example IA exceptrather than pouring the liquid bioerodible mixture on a sheet ofpolyvinyl chloride, the mixture is poured into a mold. The mold formsparticles in the shape of hemispheres (half spheres) having a thicknessof about 0.4 mm and a diameter of about 1.0 mm.

EXAMPLE V

A. Nine grams of collagen are added slowly with stirring to 40 grams ofbuffer solution at 90° C. The buffer solution includes one liter ofdistilled water, 7.1 grams of disodium hydrogen phosphate and 6.9 gramsof sodium dihydrogen phosphate monohydrate. The pH should be 6.8. FortyMl of the phosphate buffer and 0.15 grams chlorobutanol are combinedwith the heating and stirring. Alternatively, the collagen can be addedto the buffer solution after it is cooled to room temperature and themixture is then heated to 90° C. until the solution is complete.

Three grams of cyclosporin are suspended in 5 ml of phosphate buffer.The resultant mixture is added immediately to the stirred collagensolution as it cools to approximately 50° C. The mixture is stirredthoroughly for four minutes until the temperature falls to 40° C. and isthen poured onto a sheet of polyvinylchloride to a thickness which willdry to a thickness in the range of about 0.4 mm to 0.7 mm. The resultingfilm is dried at room temperature for one day.

A solution of formaldehyde (1% by weight) is prepared by addition of13.1 grams of 38 percent formaldehyde reagant to 487 grams phosphatebuffer (pH 6.8). The collagen films are submerged in this bufferedformaldehyde solution for 20 minutes at room temperature, quickly rinsedwith water and soaked in ice water for 2 hours. The films are removedfrom the ice water and dried overnight.

The dried film is then cut into individual particles using a moldcutter. The mold cutter forms disc-shaped particles having a diameter of1 mm, and a thickness of 0.4 mm which was the thickness of the driedfilm.

B. The particles are then suspended in a liquid medium made of steriledistilled water, 1% w. poly(vinyl alcohol), 0.1% cyclosporin and 0.004%benzalkonium chloride. A suspension of about 5 particles per 0.25 cc ofcarrier medium is prepared.

The suspension is then administered as described in Example IB.

Although the present invention has been described and illustrated indetail, it is to be clearly understood that the same is by way ofillustration and example only, and is not to be taken by way oflimitation. The spirit and scope of the present invention are to belimited only by the terms of the appended claims.

What is claimed is:
 1. An ophthalmic drug delivery system including acomposition comprising:one of a liquid carrier and an ointment carriercontaining ophthalmic drug to be delivered to an ocular area and havinga pH acceptable to the eye; and at least one particle of bioerodiblematerial in said carrier and including at least the same ophthalmic drugas in said carrier in the same chemical form.
 2. A system as in claim 1,wherein said particles additionally include a different drug than saiddrug in said solution.
 3. A system as in claim 1, including a pluralityof said particles, at least a portion of said particles including drugin a different concentration than at least another portion of saidparticles.
 4. A system as in claim 1, including a plurality of saidparticles, at least a portion of said particles including a differentdrug than at least another portion of said particles.
 5. A system as inclaim 1, wherein a specific equilibrium between drug in said at leastone particle and drug in said particle carrier provides a specificamount of drug to be delivered over a specific duration whenadministered to the ocular area.
 6. A system as in claim 1, wherein saidbioerodable material is at least one member selected from the groupconsisting of collagen, gelatin, polyvinyl alcohol, polymerizedmethycellulose and methyl cellulose derivatives.
 7. A system as in claim1, wherein said ophthlamic drug is at least one member selected from thegroup consisting of idoxuridine, phenylephrine, pilocarpine and itsacceptable salts, eserin, carachol, phospholine iodine, demecariumbromide, cyclopentolate, homatropine, scopolamine and epinephrine.
 8. Asystem as in claim 1, wherein said ophthalmic drug is at least oneophthalmic steroid selected from the group consisting of hydrocortisone,hydrocortisone acetate, dexamethasone, desamethasone 21-phosphate,fluocinolone, medrysone, prednisolone acetate, fluorometholone,betamethasone and triamcinoline.
 9. A system as in claim 1, wherein saidophthalmic drug is at least one antibiotic selected from the groupconsisting of tetracycline, chlorotetracycline, bacitracin, neomycin,polymyxin, granicidin, oxytetracycline, chloramphenicol, gentamycin,penicillin, erythromycin, tobra mycin, ciprofloxacin and norfloxacin.10. Process for making an ophthalmic drug delivery system including acomposition comprising:forming at least one particle of bioerodiblematerial; and suspending said at least one particle of bioerodiblematerial in one of a liquid carrier and an ointment carrier containingophthalmic drug to be delivered to the ocular area and having a pHacceptable to the eye; said at least one particle when suspendedincluding at least the same ophthalmic drug as in said carrier in thesame chemical form.
 11. A process as in claim 10, further includingadding ophthalmic drug to said at least one particle of bioerodiblematerial prior to suspending said at least one particle in said carrier.12. A process as in claim 11, wherein said adding of drug to said atleast one particle includes soaking said at least one particle in asolution containing the drug such that the at least one particle absorbsthe drug.
 13. A process as in claim 12, wherein said soaking solution isprepared with a specific concentration of drug, and said at least oneparticle absorbs a specific amount of drug depending on the specificconcentration of drug in said soaking solution.
 14. A process as inclaim 11, further including establishing a specific equilibrium betweenthe drug in said at least one particle and the drug in said carrier,thereby establishing a specific concentration of drug to be deliveredand a specific duration of drug delivery when administered to the oculararea.
 15. A process as in claim 10, wherein said suspending includesusing least one of bioerodible material which absorbs said included insaid carrier during said suspending.
 16. A process as in claim 15,further including adding ophthalmic drug to said at least one particleof bioerodible material prior to suspending said at least one particlein said carrier.